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Croat Med J. 2007 Feb;48(1):9-21.

Role of decreased sensory neuron membrane calcium currents in the genesis of neuropathic pain.

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  • 1Department of Anesthesiology, Medical College of Wisconsin, Room M4280, 8701 Watertown Plank Rd, Milwaukee, WI, USA.


The pathogenesis of neuropathic pain is incompletely understood and treatments are often inadequate. Cytoplasmic Ca(2+) regulates numerous cellular processes in neurons. This review therefore examines the pathogenic contribution of altered inward Ca(2+) flux (I(Ca)) through voltage-gated Ca(2+) channels in sensory neurons after peripheral nerve injury. We reviewed studies that recorded membrane currents through intracellular and patch-clamp techniques, as well as intracellular Ca(2+) levels using fluorimetric indicators, and performed behavioral analysis of rodent nerve injury models. Following nerve injury by partial ligation, a response characterized by sustained lifting, shaking, and licking of the paw after sharp mechanical stimulation is a reliable indicator or neuropathic pain. Primary sensory neurons isolated from animals with this behavior show a decrease in high-voltage activated I(Ca) by approximately one third. Low voltage-activated I(Ca) is nearly eliminated by peripheral nerve injury. Loss of I(Ca) leads to decreased activation of Ca(2+)-activated K(+) currents, which are also directly reduced in traumatized neurons. As a result of these changes in membrane currents, membrane voltage recordings show increased action potential duration and diminished afterhyperpolarization. Excitability is elevated, as indicated by resting membrane potential depolarization and a decreased current threshold for action potential initiation. Traumatized nociceptive neurons develop increased repetitive firing during sustained depolarization after axotomy. Concurrently, cytoplasmic Ca(2+) transients are diminished. In conclusions, axotomized neurons, especially pain-conducting ones, develop instability and elevated excitability after peripheral injury. Treatment of neuronal I(Ca) loss at the level of injury of the dorsal root ganglion may provide a novel therapeutic pathway.

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